17-beta estradiol protects esophageal epithelium from IL-13-induced barrier dysfunction and remodeling

Publication date: Available online 20 December 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Justin C. Wheeler, Simone Vanoni, Chang Zeng, Lisa Waggoner Bsc, Yanfen Yang, David Wu, Jazib Uddin, Rebekah Karns, Leah Kottyan, Vince Mukkada, Marc E. Rothenberg, Simon P. Hogan

Abstract

Background

The incidence of Eosinophilic esophagitis (EoE) is higher in males than females and the underlying molecular basis for this gender bias remains unclear.

Objective

To delineate the contribution of the sex hormone estrogen to the EoE phenotype and esophageal epithelial barrier function and remodeling.

Methods

We performed demographic and incidence analyses of EoE in males and females from a single center pediatric cohort. Estrogen responsive gene expression analyses and estrogen receptor immunofluorescence staining of esophageal biopsies from EoE patients and controls were performed. The effect of E2 on IL-13-induced signaling pathways, gene expression, and esophageal epithelial architecture and barrier function in a primary human esophageal keratinocyte culture system (EPC2-ALI) was examined.

Results

We observed a male predominance in EoE. Analyses of RNA-seq datasets revealed a significant dysregulation of the estrogen responsive gene network and expression of the estrogen receptors ESR1 and ESR2 in esophageal biopsies from EoE patients compared with controls. IL-13 stimulation of EPC2-ALI cells led to altered cellular architecture with induced dilation of intercellular spaces, and barrier dysfunction. Pretreatment of EPC2 cells with E2 prior to IL-13 exposure abrogated IL-13-induced architectural changes and esophageal barrier dysfunction. Mechanistically, E2 protective effects were dependent on ESR2 and associated with diminishing of IL-13-induced TYK2 and STAT6 phosphorylation and EoE dysregulated gene expression.

Conclusions

Estrogen responsive genes are modified in EoE patients compared to controls. E2 attenuated IL-13 induced architectural changes and esophageal epithelial barrier dysfunction via ESR2-dependent process via inhibition of the IL-13/TYK2/STAT6 pathway. Estrogen hormone signaling may protect against development of EoE in females.

Graphical abstract

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